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IGFBP

[Insulin-like growth factor binding proteins] also abbr. IGBP or IBP. IGFBPs are found in various body fluids such as blood serum, amniotic fluid, and liquor. They are synthesized in the liver and are produced also by various tumor cell lines and cell types. Some cells produce and secrete some IGFBPs constitutively and the synthesis of some IGFBPs is regulated, among other things, by the two different IGF factors themselves. The two forms of IGF also appear to promote directly the proteolytic degradation of some IGFBPs (IGFBP4) into fragments that do not bind IGF, thus providing a mechanism by which each form of IGF may increase its own availability and/or activity in biological fluids.

IGFBPs are high affinity binding proteins for IGF. The major fraction of both types of IGF circulating in the blood are bound non-covalently to these carrier proteins, forming complexes of 140-150 kDa (large complex) and 40 kDa (small complex) which may be monomeric and oligomeric (IGFBP)n complexes. Some IGFBP/IGF complexes may contain additional complexed proteins. The formation of these complexes may be inhibited by glycosaminoglycans. Both types of IGF can be released from these complexes by treatment with acids, heparin, proteases, and plasmin.

IGF binding proteins modulate IGF activities by increasing their plasma half lives and by inhibiting or promoting the interactions of IGF with receptors on certain target cells. In addition these binding proteins provide a reservoir for IGF in pericellular spaces. Some IGFBPs also have stimulating effects in vitro and some may inhibit the growth of cells (see also: IDF-45). Some granulosa cell-derived IGFBPs appear to function as antigonadotropins at the level of the ovary. Small-cell lung cancer cells have been found to produce and release IGF binding proteins that differ from those found in liver and placenta. It has been suggested that they may function as mediators in the autocrine and/or paracrine growth regulation of IGF in these tumors.

IGFBPs are cysteine-rich proteins of which various molecular forms are known that may differ also in the extent of glycosylation. They have no sequence homology with the IGF receptors. The proteins display strong sequence homologies, suggesting that they are encoded by a closely related family of genes. The number (18) and position of the cysteine residues is conserved in almost all IGFBPs. There are some indications that IGFBPs can be phosphorylated and that phosphorylation also alters their biological activities. At present at least six different IGF binding proteins are known. They differ in their binding efficiencies.

IGFBP1 is a protein of 34 kDa (= BP-34, 34 k IGFBP). 25 kDa (IGF-BP25[IGF binding protein 25]) and 28 kDa forms (25 k and 28 k IGFBP1) of this protein have been described also and probably arise by differences in glycosylation. The gene encoding this protein has a length of 5.2 kb and contains four exons. It maps to human chromosome 7p14-p12 at a distance of approximately 20 kb from the IGFBP3 gene. The transcription of the IGFBP1 gene is repressed by insulin while inhibitors of glucose uptake such as cytochalasin B enhance the synthesis of IGFBP1. Cortisol also increases plasma levels of IGFBP1 in humans. The synthesis of IGFBP1 by humanhepatoma cells is enhanced by EGF. IGFBP1 has equal affinity for IGF-1 and IGF-2. Serine phosphorylation of IGFBP1 has been shown to alter its affinity for IGF-1 and IGF-2 and to modify its capacity to modulate cellular responses to the two forms of IGF.

In the human osteosarcoma cell line MG-63, IGFBP1 can form an IGF reservoir in the pericellular space surrounding the cells by forming complexes that are incapable of binding to the IGF receptors. These complexes can be dissolved by plasmin. The secretion of plasminogen activators by osteosarcoma cells and the availability of plasminogen in the extravascular tissues may provide a regulatory system in osteosarcoma cells in which pericellular plasmin affects the availability of the two forms of IGF to their membrane receptors.

The effect of IGFBP1 depends on its phosphorylation status; phosphorylated IGFBP1 inhibits IGF actions whereas the nonphosphorylated isoform is stimulatory. alpha2M has been shown to associate preferentially with the phosphorylated isoform of IGFBP1 anf thus indirectly to modify responses of cells to IGF. These complexes still bind IGF-1. alpha2M protects IGFBP1 from proteolysis and abrogates the inhibitory effect of phosphorylated IGFBP1 on IGF-1 stimulated 3T3-L1cell proliferation (Westwood et al, 2001).

D'Ercole et al (1994) have studied transgenicmice overexpressing humanIGFBP1 in the brain. The animals show brain growth retardation, which most likely results from IGFBP1 inhibition of growth-promoting actions stimulated by IGF. These mice should prove useful in defining IGF actions during postnatal brain maturation.

IGFBP1 is found predominantly in the placenta and the amniotic fluid. The predominant sites of IGFBP1 transcription in the human fetal kidney are those with most active differentiation. Elevated serum levels have been observed in patients with Laron-type dwarfism and Growth hormone deficiency. High serum levels of IGFBP1 are found in newborns and it has been suggested that this could be important in protecting them from hypoglycemia.

IGFBP2 (27 kDa, 24 kDa; 289 amino acids) is observed mainly in brain and liquor, showing complex patterns of gene expression during postnatal brain development. Elevated levels IGFBP2 have been observed in the serum of prostate cancer patients. IGFBP2 expression does not depend on Growth hormone. The gene maps to human chromosome 2q33-q34. It contains four exons and has a length of 32 kb. IGFBP2 has been shown to be secreted by intestinal epithelial cells and to capable of limiting the mitogenic activity of both exogenous and endogenous IGF by blocking the association of the growth factors with cell surface binding sites. IGFBP2 has been implicated also in myeloblastdifferentiation. It shows preferential affinity for IGF-2.

IGFBP3(264 amino acids, 53 kDa; = BP-53) is the major IGF binding protein present in serum of humans and animals. It is also present in the alpha granules of platelets. IGFBP3 shows a similar affinity for IGF-1 and IGF-2. The mature protein is cysteine-rich and has a length of 264 amino acids. Its amino acid sequence is 33 % identical with that of IGFBP2. IGFBP3 is known also as Growth hormone dependent binding protein, acid stable subunit of the 140 K IGF complex, and Binding protein-29. The human gene has a length of 8.9 kb and contains 5 exons. It maps to chromosome 7p14-p12 in the vicinity of the IGFBP1 gene. Smaller fragments of IGFBP3 consisting of various C- or N-terminally truncated forms have been described also. A proteolytic enzyme specific for IGFBP3 has been isolated from serum of pregnant women.

The 140 kDa IGF binding protein complex in humanserum consists of three subunits: an acid-labile, non-IGF-binding glycoprotein (alpha-subunit), IGFBP3 (beta-subunit), and IGF-1 or IGF-2 (gamma-subunit). Glycosaminoglycans have been shown to inhibit complex formation without affecting the binary complex. Since the ternary IGF-binding protein complex cannot cross the capillary barrier, a decrease in the affinity of the complex, mediated by circulating or cell-associated glycosaminoglycans, may be important in the passage of IGF and IGFBP3 to the tissues.

Stimulation by serum of dense cultures of murine3T3fibroblasts rapidly induces increased synthesis of a growth inhibitor identified as murineIGFBP3. Secretion of the factor is induced also by bFGF, PDGF, and insulin. DNA synthesis stimulated by bFGF is arrested when accumulation of mIGFBP3 is maximal, suggesting that the accumulation of mIGFBP3 may induce a feedback regulation of cell growth. An involvement of IGFBP3 in negative regulation of cell growth has been suggested by studies of transgenicfibroblasts lacking the type 1 IGF receptor and overexpressing this binding factor (see: IGF, subentry Transgenic /Knock-out/Antisense Studies).

HumanIGFBP6 has a length of 216 amino acids (22.8 kDa) and is an O-glycosylated protein. It is abundant in cerebrospinal fluid and has a marked preferential binding affinity for IGF-2 over IGF-1. The gene maps to human chromosome 12. Levels of IGFBP6 (and also of IGFBP5) have been found to be increased in human breast cancer cells treated with estradiol and IGF-1 and may thus contribute to mitogenesis. Kato et al (2000) have shown that mac25 is a secreted tumor suppressor that binds to Activin A.

The designation IGFBP8 has been proposed by Kim et al (1997) for humanCTGF following the observation that this factor possesses a conserved IGFBP motif (GCGCCXXC) and binds IGF with low affinity. A 29 kDa IGFBP has been found in human bone. This protein has a much higher affinity for IGF-2 than IGF-1 and potentiates the proliferative actions of IGF-2 on bone cells.